Miriam E. Tucker

May 05, 2013

PHOENIX — Recombinant human parathyroid hormone (PTH) given subcutaneously improved mineral homeostasis and was well tolerated in a 24-week phase 3 clinical trial of 134 adult patients with hypoparathyroidism.

The condition is currently the only recognized endocrine disorder for which there is no licensed hormonal treatment. Instead, management involves the use of large doses of calcium and active vitamin D (calcitriol or 1-alpha calcitriol) to control symptoms and biochemical indices.

"The problem is they don't treat the underlying cause," said Bart L. Clarke, MD, associate professor of medicine at the Mayo Clinic, Rochester, Minnesota, who presented the findings of the randomized, placebo-controlled, multicenter REPLACE trial here at the American Association of Clinical Endocrinologists 2013 Scientific & Clinical Congress.

Recombinant human parathyroid hormone (rhPTH[1-84]) is approved in Europe for the treatment of osteoporosis but not for hypoparathyroidism, and it is not licensed in the United States. Data from REPLACE — which was sponsored by NPS Pharmaceuticals and for which headline results were first reported 18 months ago — will be submitted to the US Food and Drug Administration (FDA) with the goal of gaining an indication for hypoparathyroidism, Dr. Clarke told Medscape Medical News.

"Recombinant human parathyroid hormone will be the first hormone treatment for hypoparathyroidism if approved by the US FDA. Those patients with difficult-to-control low blood calcium will find their...levels easier to control, with significantly less calcium and vitamin-D supplementation," he said.

But R. Mack Harrell, MD, cofounder of Memorial Integrative Endocrine Surgery in Hollywood and Boca Raton, Florida, told Medscape Medical News that in his opinion, the dosing complexity and side effects seen with rhPTH[1-84] might limit its use. "Hypoparathyroid patients suffer mightily with their disease... Because of its 10- to 12-hour biologic effect, once-daily subcutaneous rhPTH[1-84] offers promise for the hypoparathyroid patient, but it is not a panacea."

However, "I believe that the data are strong enough to justify rhPTH[1-84] use in a severely affected subgroup of hypoparathyroid patients," he added.

Meaningful Reductions in Oral Calcium and Vitamin D

The REPLACE trial began with an optimization period of 2 to 16 weeks, in which calcium and active vitamin-D doses were titrated with a target of stable serum calcium levels of 8.0 to 9.0 mg/dL. After that, the patients were randomly assigned to receive either once-daily subcutaneous injections of 50-µg rhPTH[1-84] (n = 90) or placebo (n = 44), with ongoing optimization of calcium and vitamin-D supplementation.

During the next 12 weeks, doses of calcium and vitamin D were down-titrated as the dose of rhPTH[1-84] was increased to 75 µg and then 100 µg per day during the first 5 weeks, then held constant.

The primary efficacy end point was a composite of 50% or greater reduction in the needed oral calcium and active vitamin-D doses at week 24, while albumin-corrected serum calcium levels were maintained in the range of 7.6 to 10.6 mg/dL.

The proportions meeting that composite end point were 53.3% of the rhPTH[1-84]-treated group, compared with just 2.3% of the placebo group. The difference was highly statistically significant (P < .001), Dr. Clarke reported.

Secondary end points were also significantly different between the groups. Independence from active vitamin D combined with an oral calcium dose of less than 500 mg per day was achieved by 43% of the treated group vs just 5% of the control participants (P < .001).

And at week 24, oral calcium doses were reduced by 52% in the rhPTH[1-84]-treated group, whereas the dose rose by 6% among the control participants (P < .002). Active vitamin-D doses dropped by 78% in the treated group, compared with 30% in the control group (P < .009).

Yet, despite the substantial reductions in active vitamin-D and calcium doses, serum calcium levels remained near or above baseline in the treated group, with a mean drop of just 0.13 mg/dL. In contrast, serum calcium declined initially in the placebo group but then rose again as supplementation increased, Dr. Clarke noted.

Serum phosphorus levels fell by about 0.5 mg/dL in the treated group but remained unchanged from baseline in the placebo patients (P < .003).

"Replacement therapy with individualized dosing of this recombinant human PTH[1-84] allows for clinically meaningful reductions in oral calcium and active vitamin D while maintaining serum calcium concentrations in the goal range desired," Dr. Clarke concluded.

More Details on Tolerability, Adverse Effects

Dolores Shoback, MD, professor of medicine at the University of California, San Francisco, presented the safety data for rhPTH[1-84] separately. Six patients in the treatment group and 7 in the placebo group discontinued treatment, with 1 in the active group discontinuing due to treatment-related effects.

Compliance was high in the study, with 98% of the rhPTH[1-84] patients and 96% of the placebo patients administering all the prescribed doses.

Adverse events were reported by 90% of the rhPTH[1-84] group and 96% of the control participants. Serious events were far less common, 6% and 5%, respectively. The 1 serious event considered treatment-related was a case of hypercalcemia requiring brief hospitalization, she reported.

Adverse events that occurred 10% more often in the treatment vs control group included hypocalcemia (38% vs 23%), paraesthesia (34% vs 23%), and hypercalcemia (21% vs 18%). Rates of nausea were about the same in the 2 groups, 21% and 18%, respectively.

During the 4-week follow-up after the treatments were stopped, 58% of the rhPTH[1-84]-treated patients and 43% of the control patients reported adverse events. Hypocalcemia was most common, 31% vs 9%, respectively.

Serious adverse events in the posttreatment period included hypocalcemia of less than 7.5 mg/dL in 3 rhPTH[1-84] patients and in 2 control patients, and 1 patient with gallstone pancreatitis in the rhPTH[1-84] group vs none in the control group.

"rhPTH[1-84] was well-tolerated for 24 weeks, and patients were highly compliant," Dr. Shoback concluded.

Going Forward: REPLACE Will Continue Through 2014

Dr. Harrell told Medscape Medical News that the adjustment of calcitriol and calcium doses required when using rhPTH can be difficult. "If the adjustment phase is not handled properly, hypo- and hypercalcemia ensue."

And, he added, "Human PTH has the unwanted side effect of nausea and GI distress in a small subpopulation... We need to continue to work on refining the delivery mechanisms and dosing paradigms."

Dr. Clarke told Medscape Medical News that the REPLACE study patients are now being followed in an open-label extension phase with rhPTH[1-84], currently planned through the end of 2014, and those data will be included in the FDA submission.

The REPLACE study was funded by NPS Pharmaceuticals, which funded Dr. Clarke and Dr. Shoback to conduct the study. Neither has any other relevant financial relationships. Dr. Harrell is on the advisory board of LabCorp.

American Association of Clinical Endocrinologists (AACE) 22nd Annual Scientific and Clinical Congress. Abstracts 1035 and 1036, presented May 2, 2013.